Comparative kinetics of sematilide in four species

The goals of this retrospective study with the novel class III antiarrhythmic sematilide HCI were to investigate: a) whether there existed interspecies correlations and b) whether reliable animal-to-human predictions were possible for the main pharmacokinetics parameters. Information on plasma concentrations after intravenous administration was available in rats, rabbits, dogs, and humans. Except for the rabbit, data on the urinary amounts of drug excreted were also available in these species. The drug concentrations in plasma and urine were assayed by a specific HPLC method with UV or electrochemical detection or liquid scintillation spectrometry. In the interspecies correlations and in the animal-to-human predictions, an allometric approach was used with log-log linear regressions of the pharmacokinetic parameters steady-state volume of distribution (Vss), total clearance (CL), mean residence time (t), and terminal disposition half life (t1/2 lambda z), on body weight. The results showed that significant interspecies correlations exist for the tested in vivo pharmacokinetic parameters for sematilide. Reliable animal-to-human predictions with errors < 60% were found for Vss, CL, t1/2 lambda z, and t. In rats, dogs, and humans, sematilide's renal elimination includes glomerular filtration and net tubular secretion. The relative contributions of the renal mechanisms are similar in all three species studied. There were no important species differences observed in the in vitro determined parameters, fraction unbound in plasma, and blood-to-plasma concentration ratio between rats, dogs, and humans.